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Cien. Inv. Agr. 38(2):303-317.

2011
www.rcia.uc.cl
human health

literature review

The medicinal value of honey: a review on its benefits to human


health, with a special focus on its effects on glycemic regulation
Manuel E. Corts1,2, Pilar Vigil2, and Gloria Montenegro3

Departamento de Ciencias Animales, Facultad de Agronoma e Ingeniera Forestal, Pontificia Universidad


Catlica de Chile. Casilla 306-22, Santiago, Chile.
2
Unidad de Reproduccin y Desarrollo, Departamento de Fisiologa. Facultad de Ciencias Biolgicas,
Pontificia Universidad Catlica de Chile. Casilla 114D, Santiago, Chile.
3
Departamento de Ciencias Vegetales, Facultad de Agronoma e Ingeniera Forestal, Pontificia Universidad
Catlica de Chile. Casilla 306-22, Santiago, Chile.

Abstract
M.E. Corts, P. Vigil, and G. Montenegro. 2011. The medicinal value of honey: a review
on its benefits to human health, with a special focus on its effects on glycemic regulation.
Cien. Inv. Agr. 38(2): 303-317. Honey, a natural substance produced by honeybees, is
composed of a complex mixture of carbohydrates, water, and a small amount of proteins,
vitamins, minerals, and phenolic compounds. Fructose, glucose and maltose are among the
various types of sugars present in honey. Used for millennia as both food and medicine, honey
has been associated with improved antioxidant capacity, modulation of the immune system,
antimicrobial activities, influence on lipid values (through antihypercholesterolemic effects)
and regulation of glycemic responses, among other benefits. The aim of this article was to
review the effects of natural honey intake on human health, with particular reference to its
influence on glycemic regulation. Several studies have focused on the potential use of honey as
a nutritional supplement for healthy individuals and for those with impaired glucose tolerance,
diabetes, and their related comorbidities. Such investigations have found that, compared to
glucose and sucrose, the consumption of honey decreases glycemic levels and blood lipids
in healthy, diabetic and hyperlipidemic individuals. Moreover, long periods of honey intake
seem to reduce fasting glucose levels in humans, suggesting that honey consumption influences
plasma glucose regulation, mainly through a normo- or hypoglycemic effect. Therefore, honey
may be proposed as a nutritional dietary supplement for healthy individuals and for those
suffering from alterations in glycemic regulation.
Key words: Diabetes, flavonoids, glycemic regulation, honey, insulin resistance, nutraceuticals,
nutrition.

Introduction
Honey is a natural substance of sweet flavor
and viscous consistency produced by honeybees, especially by the species Apis mellifera.
Received March 12, 2010. Accepted March 23, 2011.
Corresponding author: manuelcortes@uc.cl

Honey was probably the first sweetener discovered by man, and its use dates back to the
origins of mankind itself (Havsteen, 2002); in
fact, honey reportedly constituted a component of the Paleolithic diet (Eaton and Eaton,
2000). There is evidence of the development of
beekeeping in the Neolithic, as shown in cave
paintings found in Cueva de la Araa, near
Bicorp, Valencia, Spain, which depict honey

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being collected by a prehistoric man using a


makeshift beehive. Records of its use have
been found in Sumerian clay tablets dated
21002000 years B.C. (Yaghoobi et al., 2008).
In Egypt, beekeeping underwent remarkable
development, and representative products of
the apiary (e.g., beeswax, honey, pollen, propolis, and royal jelly) were used both as medicine
and ceremonial materials, and jars containing
residues of honey and related substances have
been found in the tombs of several pharaohs
(Havsteen, 2002), such as that of Tutankhamun
(Kahn et al., 2007). In Greece and Rome, honey was also utilized as medicine and energy
food (Garca et al., 1986; Garret and Grisham,
2001); in India, it has been of great relevance
in Ayurvedic Medicine and Unani Medicine
for centuries (Aparna and Rajalakshmj, 1999;
Agrawal et al., 2007). The therapeutic effect of
honey was also known in Persia, as mentioned
by the scientist, philosopher and physician Avicenna approximately 1000 years ago in his remarkable book, Canon of Medicine (Avicenna,
1999). In Medieval Europe, beekeeping continued to develop, and later, during the Renaissance, it also inspired artists, such as the Florentine painter Piero di Cosimo, author of The
Discovery of Honey (Thomas and Mathews,
1963; Garret and Grisham, 2001). Later, in the
XVII century, the Tratado Breve sobre la Cultivacin de las Colmenas was transcribed in
Spain (de Jess Mara, 1653) and is one of the
earliest works on beekeeping to be written in
Spanish. Thus, honey has occupied an important role in the human diet from the dawn of
mankind to the present day.
Currently, honey is widely used for nourishment, constituting a nutritious supplement with
medicinal properties recognized all over the
world (Montenegro et al., 2003); this has led to
its current use in the treatment of a number of
pathologies (Molan, 2001; Kahn et al., 2007) and
justifies its nomination as a functional aliment
or nutraceutical. Honey is produced in almost
every country of the world and is recognized as
an important energy food (Muoz et al., 2007).
Because of its high nutritious value and unique
flavor, honey has become increasingly accepted
by consumers, often being used as a substitute
for other sweeteners (Montenegro et al., 2003).

Nevertheless, it is not to be considered a whole


food according to human standards but rather
as a potential dietary supplement (Muoz et al.,
2007). The world production of honey today
comprises approximately 1.2 million tons, less
than 1% the total production of sugar (lvarezSurez et al., 2010). The demand for honey varies remarkably from one country to another,
and China and Argentina rank among the main
exporters; these countries, however, have low
annual consumption rates, close to 0.1 to 0.2
kg per capita (lvarez-Surez et al., 2010). Indeed, honey consumption is higher in developed
countries, where domestic production does not
meet the market demand (lvarez-Surez et al.,
2010). In Chile, honey is produced by approximately 14,000 beekeepers, and there are over
335,000 apiaries, which produce different varieties of unifloral and polyfloral honey (Muoz
et al., 2007).
Considering the wide interest generated since
ancient times by the medicinal and nutritional
properties associated with honey, the objective of this review article was to summarize the
main benefits attributed to the intake of natural
honey, with a special focus on the effects exerted on glycemic regulation.
The composition of honey
Honey is composed of a complex mixture of water, carbohydrates and a myriad of other minor
compounds (White, 1978; Garca et al., 1986).
The chemical composition of honey is variable
and depends on regional and climatic conditions
and on the type of flowers visited by the bees,
thus, its classification as unifloral or polyfloral
(Fredes, 2004; Muoz et al., 2007; Fredes and
Montenegro, 2008). However, on average, natural honey is composed of 17.1% water, 82.4%
carbohydrates approximately 38.5% fructose,
31% glucose and 12.9 % other sugars and
0.5% proteins, amino acids, vitamins, phenolic
compounds, organic acids and multiple minerals, among other minority constituents (White,
1978; Garca et al., 1986; Garret and Grisham,
2001; Moreira and De Maria, 2001; Fredes,
2004; Fredes and Montenegro, 2006; Kahn et
al., 2007; Montenegro and Fredes, 2008). It has

VOLUME 38 N2 MAY AUGUST 2011

also been suggested that the presence of variable amounts of heavy metals can be related to
the geographical and botanical origin of this
product (Fredes, 2004; Fredes and Montenegro,
2006).
In natural honey, as well as in propolis and royal
jelly, most of the phenolic compounds are present in the form of flavonoids (Viuda-Martos et
al., 2008), a vast family of phytochemicals comprising chalcones, flavandiols, flavonols, anthocyanins and proanthocyanidins. Flavonoid biosynthesis is derived from the phenylpropanoid
pathway, one of the most widely studied secondary metabolic routes in plant systems. Several phenolic compounds, especially flavonoids,
are associated with multiple benefits on human
health, including anti-inflammatory, antioxidant, antiallergic, antithrombotic, antidiabetogenic, hypoglycemic, normolipidemic, hepatoprotective, antiviral and anticarcinogenic activities (Havsteen, 2002; Middleton et al., 2000;
Prez-Trueba, 2003). Due to these properties,
flavonoids have been recognized as nutraceutical compounds (Tapas et al., 2008). Regarding
the flavonoids identified in Chilean honeys, it is
important to highlight specific compounds, such
as chrysin, galangin, isorhamnetin, kaempferol,
myricetin, naringenin, pinobanksin, pinocembrin, quercetin, and rutin (Muoz et al., 2007;
Montenegro et al., 2009). The specific effects of
these compounds on glucidic metabolism will
be described further below.

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Honey has been linked to several benecial


effects on human health
As mentioned above, for millennia honey has
been credited with multiple medicinal properties (Figure 1). In the following section, some
of these properties are explained in more detail.
Enhanced antioxidant activity
It is known that free radicals and reactive oxygen species (ROS), such as hydroperoxyl, hydroxyl, and superoxide, are associated with aging and disease mechanisms. ROS can produce
oxidative damage in biomolecules, such as carbohydrates, lipids, proteins and nucleic acids,
which can alter various cell processes and cause
cell death (Viuda-Martos et al., 2008). Several studies have found that the consumption of
honey can improve the defenses against oxidative stress (Al-Mamary et al., 2002; Schramm
et al., 2003; Beretta et al., 2007; van der Berg
et al., 2008). This function has been attributed
to the natural phenolic compounds (e.g., flavonoids) in honey (Prez-Trueba, 2003; Schramm
et al., 2003; van der Berg et al., 2008). These
phytochemicals appear to exert their antioxidant capacities mainly through the decrease and
removal of ROS, thus diminishing the risk of
pathologies and damage produced by free radicals (Beretta et al., 2007). The exact molecular

Figure 1. Main effects on human health attributed to natural honey intake.

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mechanisms of antioxidant activity of the phenolic compounds present in honey and related
beehive products are not yet fully understood.
However, the most probable ones include free
radical scavenging, hydrogen donation, the interference with propagation reactions or inhibition of enzymatic systems involved in initiation
reactions, metallic ion chelation, and acting as
a substrate for diverse free radicals, especially
ROS (van Acker et al., 1996; Al-Mamary et al.,
2002; Havsteen, 2002; Middleton et al., 2000;
Viuda-Martos et al., 2008).
Effects on the immune system
It has been suggested that the consumption of
honey can exert several beneficial effects on the
human immune response and on its associated
mechanisms. In fact, honey has been reported
to promote the multiplication of human peripheral blood B- and T-lymphocytes and the activation of neutrophils under conditions of cell culture (Abuharfeil et al., 1999). In monocytic cell
line culture, honey has been shown to stimulate
the release of inflammatory cytokines, such as
tumor necrosis factor-alpha, interleukin-1 and
interleukin-6 (Tonks et al., 2003), which are
involved in triggering a number of functions
of the immune response to infection (Molan,
2001). Moreover, in mice, it has been found
that the intake of a honey-supplemented diet
stimulates the production of antibodies during
the primary and secondary immune responses
against thymus-dependent and -independent antigens (Al-Waili and Haq, 2004). A recent study
reported an immuno-modulatory potential of
honey in the course of phagocytosis, mainly by
modifying the oxidative burst process through
the inhibition of phagocytic myeloperoxidase
activity and an inhibitory effect exerted by the
major sugar constituents of honey on exocytosis-associated ROS formation catalyzed by myeloperoxidase (Mesaik et al., 2008).
Antimicrobial activity
Honey and beehive-related substances have
been used as antiseptic agents (e.g., propolis) since at least the time of Aristotle (Molan,

2001). Despite the evident antimicrobial capacity of honey, as determined by its effective inhibition of bacterial and fungal proliferation and
growth, there does not seem to be any clear-cut
cause, suggesting that it could correspond to a
combined or synergic effect of the antioxidant
compounds present (Viuda-Martos et al., 2008).
The following properties have been proposed
to explain the effect of honey against bacterial
growth: (i) the presence of hydrogen peroxide,
resulting from the action of the glucose-oxidase
enzyme on glucose in presence of oxygen (Garca et al., 1986; Wahdan, 1998; Molan, 1999a,
Khan et al., 2007), a compound whose activity
appears to decrease as honey remains in storage
(Montenegro et al., 2009); (ii) inherent physicochemical properties, such as its high sugar
content (~80% w/w) that can produce a high osmotic effect and its acid pH of 3 to 4.5 (Molan,
1992; Bogdanov et al., 1997); (iii) the presence
of diverse organic acids (Aparna and Rajalakshmj, 1999), including gluconic acid (also derived from glucose catalysis), which remarkably
creates an acidic microenvironment and whose
concentration varies considerably from one type
of honey to another (White et al., 1963; White,
1978); and (iv) non-peroxidic substances (Cabrera et al., 2006), such as polyphenols, which
possess antibacterial activity. These compounds
vary depending on the plant species from which
the bees gather their nectar (Cooper, 2007) and
seem to remain unaltered even after long periods of storage (Viuda-Martos et al., 2008). With
regard to the antibacterial activity, it has been
recently determined that extracts of unifloral
honeys from the endemic Chilean tree, Quillay (Quillaja saponaria), which contain several
natural phenolic compounds, show antibacterial
activity against Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus, Salmonella typhi, Streptococcus pneumoniae type , and
Vibrio cholerae, and antifungal activity against
Candida albicans (Montenegro et al., 2009).
Lastly, due to its antimicrobial properties, the use
of natural honey has also been recommended in
medical treatments for promoting wound disinfection and healing (Khan et al., 2007). Thus, some
physicians have also advised their patients to use
honey to improve the healing of surgical scars
(Molan, 1999b; Molan, 2001; Khan et al., 2007).

VOLUME 38 N2 MAY AUGUST 2011

Effects on glycemic regulation


The term glycemic regulation, also known as
glycemic homeostasis, refers to diverse phenomena leading to the adequate regulation of
blood glucose levels (i.e., glycemia), which constitutes one of the mechanisms used by organisms to maintain the properties of their internal
milieu constant. For decades, there has been
interest in determining the effects of honey intake on glucose regulation disorders, and controversial results have been obtained. On the
one hand, it has been considered that honey
consumption by diabetics is pointless because
it contains a considerable proportion of sugars
(White, 1978; Moreira and De Maria, 2001),
while on the other hand, some research has produced interesting results positioning honey as
a potential nutritional supplement for subjects
with disorders of glucose homeostasis (Bornet
et al., 1985; Samanta et al., 1985; Katsilambros
et al., 1988; Shambaugh et al., 1990; Al-Waili,
2004; Agrawal et al., 2007; Ahmad et al., 2008).
Before referring to the effects of honey intake
on the alterations in glycemic regulation, it is
necessary to examine such disorders in detail,
as described below.
a. Disorders of glucose regulation and their
associated comorbidities. There can be as
many alterations in glucose metabolism as the
existing mutations in some of the enzyme-encoding genes associated with their metabolic
pathways, e.g., deficiency of phosphofructokinase-1, hepatic fructose 1,6-biphosphate aldolase or ketohexokinase. These pathologies are
commonly termed inborn errors of glucidic
metabolism (Hall, 2003). However, the most
relevant disorders that are recognized today as
related to glucidic homeostasis are those linked
to alterations in the regulation of glycemia by
insulin. Insulin is a peptide hormone produced
in the pancreas, specifically by pancreatic-beta
cells; it is composed of 51 amino acids, and the
gene that encodes it is located in chromosome
11 in humans (Vincent-Desplanques et al.,
2005). Insulin has multiple functions in an organism, such as protein and hepatic glycogen
synthesis, triacylglycerol storage in adipose
tissue, and, probably the most important func-

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tion, the regulation of glycemic levels, which


promote glucose uptake by its target cells, especially in muscle, the liver and adipose tissue.
To exert this function, insulin must bind to its
plasma membrane receptor and trigger a cascade of intracellular signaling, which eventually leads to the translocation of glucose transporters, mainly GLUT4, to the plasma membrane, resulting in glucose uptake.
When a certain amount of insulin is secreted
by the pancreas, the corresponding effector organ responds depending on its insulin sensitivity (Ferrannini and Mari, 1998). Defects in this
mechanism lead to a pathophysiological state
known as insulin resistance, which has been defined as a condition in which a normal insulin
concentration produces an attenuated biological
effect in terms of glucidic homeostasis (Yalow
and Berson, 1970), decreasing the ability of
this hormone to exert its functions on its aforementioned typical target tissues. When insulin
cannot exert its normoglycemic actions, blood
glucose can increase to dangerous concentration levels and, additionally, be accompanied by
compensatory hyperinsulinemia (i.e., excessive
circulating insulin) to diminish the increased
glucose levels (Cordain et al., 2003). The latter
constitutes one of the initial stages of diabetes
mellitus. Several types of insulin resistance
have been reported (Vincent-Desplanques et
al., 2005), a condition also linked to the development of diverse pathologies, such as obesity,
as insulin is a fundamental regulator of virtually every aspect of adipocyte biology (Khan
and Flier, 2000). This hormone promotes the
storage of triacylglycerols in adipocytes via a
number of mechanisms, which include the differentiation from preadipocytes to adipocytes.
Moreover, in mature adipocytes, insulin stimulates the transport of glucose and the synthesis
of triacylglycerols a phenomenon known as
lipogenesis and inhibits lipolysis (Khan and
Flier, 2000). In addition, insulin increases the
uptake of fatty acids derived from circulanting
lipoproteins by stimulating the activity of the
lipoprotein lipase, in adipose tissues (Khan and
Flier, 2000).
Currently, the pathology known as insulin resistance has acquired remarkable importance

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because it has been proposed to be a crucial


component of what is known as metabolic
syndrome, which consists of the combination of several pathologies or risk factors in a
single individual, increasing the susceptibility
to cardiovascular disease and diabetes. Yet,
a portion of the scientific community is still
debating on whether to consider insulin resistance a component and/or diagnostic criterion
of metabolic syndrome (Reaven, 2006). In any
case, metabolic diseases have a high prevalence in society today. This is especially true
for diabetes, the main endocrine illness worldwide, with 150 million reported diabetics, and
estimates indicate this number could double by
2025 (King et al., 1998). Factors, such as genetic predisposition, a sedentary lifestyle and
stress, are implicit in the genesis of diabetes,
together with a high-calorie diet based mainly
upon the intake of excessively fatty or sweet
food; indeed, it is known that the consumption
of food with a high-sugar content often constitutes one the central causes of the origin of
several endocrine-metabolic disorders (Cordain et al., 2003). In this respect, the prominent French physiologist and physician, Claude
Bernard, suggested in the XIX century that the
sensitivity to carbohydrates could be modulated by dietary intake (Shambaugh et al., 1990).
Thus, increasing the level of sucrose would
lead to a deterioration of glucose tolerance and
trigger harmful health effects (Shambaugh et
al., 1990).
There is also an existing link between alterations in glucose and insulin levels and several
reproductive problems in humans (Zitzmann,
2009). Insulin resistance is considered an important factor linked to ovulatory dysfunction
in women (del Ro et al., 2006; Vigil et al.,
2007a) and to hypogonadism and associated
disorders in men (Contreras et al., 2006; del
Ro et al., 2007; Zitzmann, 2009). Additionally,
impaired glucose tolerance and obesity, among
other factors related to insulin resistance in
women, also have a negative impact on fertility
(del Ro et al., 2006; Vigil et al., 2007a; Vigil
et al., 2007b). As to the latter, several studies
have reported that such endocrine-metabolic
pathologies and their comorbidities are associated with polycystic ovary syndrome, a disorder

defined as an ovulatory dysfunction caused by


hyperandrogenism, which is highly prevalent
worldwide among reproductive-aged women
(del Ro et al., 2006; Vigil et al., 2007a; Vigil
et al., 2007b).
b. Effects of honey intake on glycemic regulation. A number of studies have focused on this
topic, and among them, Samantha et al. (1985)
have shown that the intake of honey has a lower
hyperglycemic response, as compared to glucose and sucrose, in healthy or type 1 diabetic
individuals. Later, Bornet et al. (1985) have
studied subjects suffering from diabetes mellitus type 2, and found that honey, compared to an
isoglucidic amount of bread, presented no additional hyperglycemic effect in the diabetic individuals when consumed for breakfast (Bornet et
al., 1985). In relation to this, yet another study
has reported that, rather than producing a higher postprandial hyperglycemic effect, honey
causes a hyperglycemia similar to that produced
by consuming bread in individuals with type 2
diabetes (Katsilambros et al., 1988). Shambaugh
et al. (1990) have studied non-diabetic subjects
and reported that honey has a lower effect on
increasing the levels of sugar in the blood, compared to sucrose; in addition, these authors have
suggested that honey would cause fewer longterm health problems than fructose or sucrose,
in part because it contains nutrients other than
carbohydrates (Shambaugh et al., 1990; Shambaugh et al., 1991). Moreover, honey is sweeter
that sucrose, thus, a smaller amount is required.
Considering these advantages, the above authors have suggested that it should be favored
as sweetener instead of sucrose (Shambaugh et
al., 1990). Another study found that honey intake, when compared to glucose and sucrose,
resulted in reduced glucose levels, blood lipids
and C reactive protein (CRP) a marker of inflammation and oxidative damage in healthy,
diabetic and hyperlipidemic subjects (Al-Waili,
2004). Agrawal et al. (2007) have reported that
individuals with reduced glucose tolerance or
mild diabetes, who were subjected to an oral
glucose tolerance test one day and an oral honey
tolerance test the next day, showed a higher tolerance to honey, indicating that honey could be
a valuable substitute for sugar for people suffering from these metabolic pathologies (Agrawal

VOLUME 38 N2 MAY AUGUST 2011

et al., 2007). More recent studies support the


findings of the latter and have reported that
physiological glycemic responses were significantly lower in subjects who consumed natural
honey, compared to those who consumed glucose or artificial honey (Ahmad et al., 2008).
Moreover, another recent study has shown that
a regimen of a 30-day honey intake seems to
slightly reduce fasting blood glucose levels in
humans (Yaghoobi et al., 2008).
c. How could honey be exerting regulatory effects on glycemic responses? The modulation of
glycemic responses (normoglycemic and hypoglycemic effects) observed after natural honey
intake could be based on diverse mechanisms
of action that have not yet been completely elucidated. Honey contains many trace elements,
such as antioxidants, copper, zinc, and unidentified components (White, 1978; Fredes, 2004;
Fredes and Montenegro, 2006; Montenegro and
Fredes, 2008); in addition, its fructose and glucose content can play an important role in such
effects (Yaghoobi et al., 2008). The various putative underlying explanations are the following.
1) A slow decrease in saccharide absorption in
the intestine is caused by the presence of glycemic carbohydrates in natural honey (Southgate
1995; Vosloo, 2005; Ahmad et al., 2008); in addition, fermentable and non-fermentable carbohydrates from natural honey could be linked to
the modulation of intermediary metabolism in
the intestinal lumen (Wang and Gibson, 1993;
Kok et al., 1998; Shamala et al., 2000; Chow,
2002; Ahmad et al., 2008). It has been argued
that the glucose component in honey is poorly
absorbed by the gut epithelium (Agrawal et al.,
2007). Furthermore, the presence of certain
sugars, such as palatinose (isomaltulose), would
interfere with glucose absorption (Oizumi et al.,
2007). Thus, possible differences in carbohydrate absorption could also result in differences
in glycemic control (Chepulis, 2007). 2) The effect is due to the hydrogen peroxide present in
honey, which has been reported as an agent that
can effectively mimic the function of insulin
(Hayes and Lockwood, 1987), even though there
is no evidence yet to prove that hydrogen peroxide is absorbed in the gut or that the levels produced are sufficient to activate insulin receptors
(Chepulis, 2007). 3) Some compounds, which

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may also possess insulin-like activity, from the


hypopharyngeal glands of honeybees are added
to honey (Mnstedt et al., 2009a). 4) The influence of honey on glycemic control is through
its effects in decreasing prostaglandin and increasing nitric oxide (NO) levels (Yaghoobi et
al., 2008). This mechanism may participate in
glycemic modulation, as it has been shown that
prostaglandinE2 is one of the main physiological inhibitors of insulin (Cheng et al., 2003), and
higher levels of NO stimulate the increase of insulin secretion (Smukler et al., 2002). 5) There
is an antioxidant activity exerted by some nonsugar components of honey, specifically, natural phenolic compounds, such as flavonoids. Regarding the antioxidant effects of flavonoids, it
has recently been reported (Sharma et al., 2008)
that rats with streptozotocin-induced diabetes
showed a decrease in their postprandial glycemic responses after the administration of extracts of E. jambolana seeds, which have been
attributed with antidiabetogenic, hypoglycemic
and hypolipidemic effects (Sharma et al., 2008).
Interestingly, extracts from this medicinal Hindu plant possess the compounds, rutin, myricetin, quercetin and kaempferol (Sharma et al.,
2008), and, as mentioned above, these are some
of the compounds identified in natural honey
(Muoz et al., 2007; Viuda-Martos et al., 2008;
Montenegro et al., 2009). Various studies using
mainly mice and rats as experimental models
have shown that such flavonoids exert diverse
normoglycemic effects and lead to a lower incidence of complications associated with diabetes (Lee et al., 2005; Fang et al., 2008; Zanatta
et al., 2008; Fernandes et al., 2009; Kobori et
al., 2009). In particular, it has been shown that
chrysin and chrysin-derived compounds have
hypoglycemic effects in diabetic mice (Shin
et al., 1999). The polyhydroxylated flavonol,
myricetin, has also been associated with the
stimulation of lipogenesis and glucose transport
in rat adipocytes (Ong and Khoo, 1996); it has
been speculated that such a compound may exert an influence on the treatment of non-insulindependent diabetes mellitus (Ong and Khoo,
1996; Ong and Khoo, 2000). Kaempferol could
act on multiple molecular targets to ameliorate
hyperglycemia, including acting as a partial
agonist of peroxisome proliferator-activated receptor gamma (Fang et al., 2008), whereas its

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derivative, kaempferol 3-neohesperidoside, has


shown to possess an insulinomimetic effect in
rat muscle (Zanatta et al., 2008). In addition,
quercetin has also been linked to an improvement in glucose uptake (Fang et al., 2008) and
diabetes-related symptoms in rats (Kobori et al.,
2009), with similar results having been found in
rutin-administered rats (Fernandes et al., 2009).
In addition, isorhamnetin-3-O-beta-D-glucoside, a compound derived from flavonol isorhamnetin, also reportedly found in Chilean natural honeys (Montenegro et al., 2009), has proven
to be effective in the prevention or treatment of
diabetes-associated complications in various rat
tissues (Lee et al., 2005). Apigenin, another flavonoid found in honey and related substances
(Viuda-Martos et al., 2008), has shown to decrease hyperglycemia, disease-provoked thyroid dysfunction and lipid peroxidation in alloxan-treated diabetic mice (Panda and Kar, 2007).
Lastly, naringenin has been shown to prevent
dyslipidemia and hyperinsulinemia in low-density lipoprotein (LDL) receptor-null mice with
diet-induced insulin resistance (Mulvihill et al.,
2009). The aforementioned evidence leads to
the idea that such flavonoids, which are present
in natural honey, could be exerting their antidia-

betogenic, normoglycemic and normolipidemic


properties at a molecular signaling level (Middleton et al., 2000; Havsteen, 2002; Sharma et
al., 2008), mainly by decreasing the alterations
caused by oxidative stress. The latter can be understood in light of the increasing acceptance
by the scientific community that an imbalance
in the oxidative state, such as that induced by
abnormal ROS levels, is a phenomenon linked
to cellular insulin resistance, dysglycemias and
related pathologies (Evans et al., 2005; Eriksson, 2007; Martnez-Hervas et al., 2008; Choi
et al., 2008). ROS accumulation can lead to the
inadequate activation of stress kinases, damage
in cellular membranes, dysfunction in organelles, such as the endoplasmic reticulum and
mitochondria, and in the genome (Muoio and
Newgard, 2004; Eriksson, 2007; Choi et al.,
2008). In addition, inadequate oxidative modification of cell carbohydrates, lipids and proteins
can have functional consequences contributing
to the development and progression of insulin
resistance (Evans et al., 2005). Regarding the
above, the flavonoids or other phenolic compounds present in the various types of natural
honeys could be exerting their effects on glycemic control at an intracellular level by decreas-

Figure 2. One of the proposed hypothetical mechanisms through which several antioxidants (mainly flavonoids and
other phenolic compounds), which are present in natural honey, may act against the development of glycemic regulation
disorders by decreasing the oxidative stress caused by metabolic alterations, such as hyperglycemia, hyperinsulinemia
and dyslipidemia.

VOLUME 38 N2 MAY AUGUST 2011

ing the oxidative alterations linked to insulin


resistance, hyperglycemia and other associated
pathophysiological states (Figure 2). 6) It is possible that flavonoids could directly stimulate an
otherwise weak insulin effect in various ways,
for example, by directly influencing phosphokinase proteins (Havsteen, 2002). 7) Lastly, in
a similar way as mentioned above for carbohydrates, the flavonoids present in honey could
also be directly blocking carbohydrate transport at the intestine level. This is remarkably
interesting regarding the treatment of diabetes
from a pharmacological point of view. By measuring saccharide transport in Xenopus laevis
oocytes (Kwon et al., 2007), myricetin, fisetin,
and quercetin, and their glycoside precursor,
isoquercitrin, compounds which are all present in beehive products (Viuda-Martos et al.,
2008), have been reported to initiate a strong
inhibition of the fructose and glucose transport
mediated by GLUT2 (Kwon et al., 2007).
Nevertheless, the aforementioned explanations
do not exclude the possible mediation of the
beneficial effects of honey intake on glucose
homeostasis disorders by other mechanisms not
yet described.
Effects on lipid homeostasis
A few studies have focused on the influence of
oral honey consumption on the regulation of human lipid values (Al-Waili, 2004; Yaghoobi et
al., 2008; Mnstedt et al., 2009b). It has been
reported that, even though a single dose of glucose or artificial honey (consisting of 40 g fructose + 35 g glucose in 250 mL water) leads to an
increase in cholesterol and triacylglycerols 1 to
3h later, this effect is not observed with natural
honey (Al-Waili, 2004). Furthermore, a 15-day
daily intake of 75 g of honey by hyperglycemic
and hyperlipidemic individuals has resulted in a
decrease of plasma glucose, lipid levels and CRP
(Al-Waili, 2004). Another study using honeydew honey with a high antioxidant content has
indicated that HDL cholesterol increased significantly in rats fed the honey, compared to that
of the group fed on a sugar-free diet (Chepulis,
2007; Chepulis and Starkey, 2008). However, it
has been reported that a 30-day natural honey

311

intake in overweight or obese human subjects


caused a non-significant decrease in cholesterol
(Yaghoobi et al., 2008). Lastly, a recent study
of male and female subjects who randomly received a 75-g honey solution or a sugar solution
similar to honey for 14 days has shown that the
male LDL-cholesterol values were not significanly reduced by the honey supplementation;
however, in women, these values increased in
the group that received the sugar solution but
not in that fed honey (Mnstedt et al., 2009b).
Therefore, female LDL-cholesterol values may
be slightly reduced by substituting sugar with
honey in the daily diet, evidencing an antihypercholesterolemic effect as a result of honey
consumption (Mnstedt et al., 2009b).
The mechanisms through which honey exerts
this modulation on lipid values are not yet fully
understood. However, it is worth considering
that the mechanisms inherent to lipid homeostasis are intimately linked to those of glycemic homeostasis; in fact, both are occasionally
referred to as energy homeostasis. Thus, the
explanations regarding the effects exerted by
honey consumption on lipid values are closely
related to those mentioned above for the action
of honey intake on glycemic regulation. Considering the high current worldwide prevalence of
lipid profile alterations, highly associated with
the development of cardiovascular pathologies
and metabolic disturbances, the aforementioned
evidence would suggest that honey could be
used as a nutritional supplement to enhance the
lipid values of those individuals suffering from
these pathologies.
Concluding remarks
The aim of this review was to summarize the
main benefits attributed to the intake of natural honey, with special emphasis on the effects
exerted on glycemic regulation. The endocrinemetabolic pathologies mentioned here (e.g., impaired glucose tolerance, insulin resistance, diabetes, and obesity) have been shown to be currently increasing in prevalence and incidence
all over the world (Braguinsky, 2002; Cordain
et al., 2003). This increase may reflect, in part,
a rather sedentary lifestyle and the effects gen-

312

ciencia e investigacin agraria

erated by changes in the nutritional pattern


experienced by worlds population in the past
few decades. It is known that diet exerts a significant role in plasma glucose modulation and
insulin levels (Marsh and Brand-Miller, 2005);
however, regardless of the significance of this
fact, there has been a lack of knowledge with
regard to dietary management for subjects suffering from such disorders, and studies have
been focused on promoting energy-restricted
diets rather than on modifying the diet composition per se (Marsh and Brand-Miller, 2005). It
has been argued that individuals suffering from
problems affecting glycemic regulation cannot
base their diet on the same nutritional pattern
as the healthy population because such patterns
include foodstuffs that promote or aggravate
those pathologies. Avoiding the intake of sugars
and sweets has been found to be particularly advisable to maintain an adequate plasma glucose
level. However, this seems somewhat pointless,
considering that carbohydrates constitute an
important component of the diet, as glucose is
the main source of energy for the central nervous system (Agrawal et al., 2007). Regarding
the latter, it should be of great interest for agricultural, food, nutritional and health sciences to
be able to implement nutritional alternatives to
provide these individuals with functional food
supplements with medicinal properties, especially as related to glycemic regulation. Natural
honey, with therapeutic qualities widely recog-

nized worldwide, should be among these supplements.


Despite the interesting evidence presented here,
the topic merits further research, particularly with
regard to understanding the specific mechanisms
of action through which natural honey intake may
be modulating glycemic responses. Further studies should determine and investigate those underlying mechanisms based on the impact their understanding may have in medical and nutritional
approaches for individuals with glucose regulation disorders. Our research group is currently
working towards the elucidation of this topic.
Acknowledgements
M. E. Corts thanks Comisin Nacional de
Investigacin Cientfica y Tecnolgica (CONICYT, Chile) and Facultad de Agronoma e Ingeniera Forestal, Pontificia Universidad Catlica
de Chile, for the scholarships granted for Ph.D.
studies in Agricultural Sciences. The authors
also wish to thank the Fondo Nacional de Desarrollo Cientfico y Tecnolgico (FONDECYT-REGULAR 2011), for funding within the
scope of the project: Bioindicators of botanical and geographical origin of Chilean endemic
honeys, Project 1110808 to G. Montenegro.

Resumen
M.E. Corts, P. Vigil y G. Montenegro. 2011. Valor medicinal de la miel: beneficios en la
salud humana, con especial referencia en sus efectos sobre la regulacin glicmica. Cien.
Inv. Agr. 38(2): 309-323. La miel de abejas es una substancia natural constituida por una mezcla
compleja de carbohidratos, agua y una pequea proporcin de protenas, vitaminas, minerales
y compuestos fenlicos, entre otros constituyentes minoritarios. Utilizada por milenios como
alimento y medicina, se le atribuye un sinnmero de efectos beneficiosos, a saber: aumento
de la capacidad antioxidante, modulacin del sistema inmune, actividad antimicrobiana,
influencia sobre los niveles lipdicos mediante efectos antihipercolesterolmicos y regulacin
de las respuestas glicmicas, entre otros. Considerando lo anterior, nuestro objetivo es mostrar
los efectos de la ingesta de miel sobre la salud, con especial atencin en su influencia sobre
la regulacin glicmica. Diversos estudios han investigado si la miel puede constituir un
suplemento nutricional, tanto para individuos saludables como para aqullos con tolerancia
reducida a la glucosa, diabetes y comorbilidades asociadas. Estas investigaciones han

VOLUME 38 N2 MAY AUGUST 2011

313

encontrado que el consumo de miel, en comparacin a glucosa y sacarosa, disminuye los


niveles glicmicos y los lpidos sanguneos en sujetos saludables, diabticos e hiperlipidmicos.
Ms an, su ingesta durante perodos prolongados puede reducir, segn algunos estudios, los
niveles glicmicos en ayunas. Esta evidencia sugiere que el consumo de miel influencia los
mecanismos de regulacin de los niveles de glucosa plasmtica, principalmente mediante un
efecto normo- o hipoglicemiante. Segn lo anterior, la miel podra constituir un suplemento
nutricional en la dieta de individuos saludables y en aqullos con alteraciones en la regulacin
glicmica.
Palabras clave: Compuesto nutracutico, diabetes, flavonoides, miel, nutricin, regulacin
glicmica, resistencia insulnica.

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